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The Egyptian Rheumatologist (2015) 37, S33–S41
HO ST E D BYEgyptian Society of Rheumatic Diseases
The Egyptian Rheumatologist
www.rheumatology.eg.netwww.elsevier.com/locate/ejr
ORIGINAL ARTICLE
Assessment of left ventricular function in systemic
lupus erythematosus patients by speckle tracking
echocardiography: Relation to circulating
endothelial progenitor cells
* Corresponding author at: 10th El-Hekma Street, El-Mariottiah,
Haram, Egypt. Tel.: +20 237624776, mobile: +20 1223616821.
E-mail address: [email protected] (M. El Basel).
Peer review under responsibility of Egyptian Society of Rheumatic
Diseases.
http://dx.doi.org/10.1016/j.ejr.2015.05.0021110-1164 � 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Rheumatic Diseases.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Sameh W.G. Bakhoum a, Mohamed El Basel b,*, Alshaimaa R. Alnaggar b,
Mona S. Hamdyc, Hanan Hussein
d
a Cardiology Department, Faculty of Medicine, Cairo University, Egyptb Internal Medicine Department, Faculty of Medicine, Cairo University, Egyptc Clinical Pathology Department, Faculty of Medicine, Cairo University, Egyptd Rheumatology Department, Faculty of Medicine, Cairo University, Egypt
Received 5 May 2015; accepted 15 May 2015Available online 10 June 2015
KEYWORDS
Systemic lupus
erythematosus;
Endothelial progenitor cells;
Left ventricular function;
Speckle tracking
echocardiography
Abstract Background: Systemic lupus erythematosus is an autoimmune disease associated with
reduced number and impaired function of endothelial progenitor cells (EPCs) responsible for
vascular regeneration.
Aim of the work: to assess left ventricular (LV) function of SLE patients using relatively new
speckle tracking echocardiography (STE) and examine the relation of any detected abnormalities
with peripheral circulating EPC level.
Patients and methods: Fifty SLE patients and 25 healthy controls were subjected to quantifica-
tion of peripheral circulating Cluster of differentiation133+/vascular endothelial growth factor
receptor2+(CD133+/VEGFR2+) and CD34+/VEGFR2+ EPCs, transthoracic echocardiography
(TTE), tissue Doppler imaging (TDI) and STE.
Results: Patients showed a significantly lower CD133+/VEGFR2+ EPCs (p= 0.009) and
CD34+/VEGFR2+ EPC counts (p= 0.0001) compared to controls. TTE/TDI revealed a signifi-
cantly lower LV ejection fraction (EF) (p= 0.007), higher LV end systolic dimensions
(p= 0.02), myocardial performance index (MPI) (p= 0.0001) and mitral flow E/lateral annulus
E0 ratio (p= 0.002) in patients compared to controls. STE showed a significantly lower global
longitudinal strain (GLS) (p< 0.001), global circumferential strain (GCS) (p< 0.001) and global
S34 S.W.G. Bakhoum et al.
strain rate during isovolumic relaxation period (GSRivr) (p= 0.01) in patients compared to con-
trols. By multiple logistic regression analysis, the independent variables affecting GCS and
GSRivr were the prednisolone dose and the LVEF respectively. (95% CI = �0.46 to �0.03;p= 0.03 and 95% CI = 0.001–0.01; p= 0.021; respectively). There was no significant correlation
of the GLS, GCS or GSRivr with the EPCs.
Conclusion: STE detected subclinical systolic and diastolic abnormalities of LV function in SLE
patients. These abnormalities of LV function did not show however any relation with the signifi-
cantly lower EPC count detected in patients.
� 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Egyptian Society of Rheumatic
Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
1. Introduction
Systemic lupus erythematosus (SLE) is an autoimmune diseaseassociated with markedly increased atherosclerotic cardiovas-cular risk [1]. Young women with lupus are over 50 times morelikely to have a myocardial infarction compared to a
population-based sample of women of similar age [2].Endothelial dysfunction was found to significantly contributeto this accelerated atherosclerotic process, independently of
other classic risk factors of coronary artery disease (CAD) inSLE patients [3].
Anti-endothelial cell antibodies have been detected in
autoimmune diseases and were found to induce endothelial cell(EC) apoptosis [4,5]. Endothelial progenitor cells (EPCs) rep-resent a heterogeneous group of cells released from the bone
marrow into the circulation and are thought to contribute tovascular homeostasis and endothelial repair [6,7]. A study byEbner et al. [8], demonstrated that circulating mature EPCs(CD34+/VEGFR2+) in the peripheral blood of SLE patients
are reduced in number, together with increased apoptosis,impaired differentiation and a reduced migratory capacity.The diminished number and the altered functionality of these
mature EPCs reduce the ability to repair vascular damage.The number of EPCs was also found to be reduced, in heartfailure (HF) irrespective of its etiology [9]. Several abnormali-
ties of left ventricular (LV) systolic and diastolic function andincreased LV mass have been described in SLE patients[10–12]. Whether the inherent endothelial dysfunction andthe abnormalities of EPC mobilization in SLE contribute to
this LV dysfunction is uncertain.Speckle tracking echocardiography (STE) is a relatively
new technique that provides accurate quantitative evaluation
of regional and global LV function independent of the insona-tion angle and cardiac translational movements [13]. Theobjective of this study was to detect subclinical LV dysfunction
in SLE patients without clinically evident cardiovascular (CV)disease using STE and correlate possible LV function abnor-malities to circulating EPC count.
2. Patients and methods
In this prospective cross sectional study, a total of 50 SLE
patients out of 75 patients screened for the inclusion and exclu-sion criteria were recruited from the outpatient clinic or theinpatient section of the Internal Medicine and Rheumatologyand Rehabilitation Departments of Kasr Al-Ainy Cairo
University Hospitals. They were enrolled in the study between
July and September 2013. Inclusion criteria were patientsbetween 20 and 65 years of age with a diagnosis of SLE who
fulfilled at least 4 of the updated revised criteria of theAmerican College of Rheumatology for SLE diagnosis [14].Exclusion criteria were patients with hypertension defined as
a systolic blood pressure (BP)P 140 mmHg or diastolicBPP90 mmHg or on antihypertensive medication, diabetesmellitus defined as a fasting blood glucose P126 mg/dl or 2-
h post-load glucose P200 mg/dl [15], history of smoking, orsignificant valvular heart disease. Twenty-five healthy ageand gender matched subjects served as controls. The researchprotocol was approved by the ethics committee of Cairo
University Hospital. The study was conducted in accordancewith the Declaration of Helsinki. Written, informed consentwas obtained from each patient.
The disease activity was assessed using the SLE diseaseactivity index (SLEDAI) scoring system [16]. Information con-cerning disease duration and medications used was recorded.
A blood sample was collected from all patients and controlsfor EPC count estimation in addition to routine laboratoryworkup including complete blood count, high sensitivity C-
reactive protein (HsCRP) estimated by ELISA, erythrocytesedimentation rate (ESR), renal function tests, total choles-terol and triglyceride levels, fasting blood glucose, anti-nuclear antibodies (ANA), and anti-double stranded deoxyri-
bonucleic acid antibodies (Anti ds-DNA).
2.1. EPC identification and counting by flow cytometry (FC)analysis
Phycoerythrin (PE)-labeled monoclonal anti-CD34 & anti-CD133 (Cat. No. 130-081-002; Miltenyi Biotec, Germany),
fluorescein-labeled monoclonal anti-VEGFR2/KDR (Cat.No. FAB357F; R&D/UK) were used for the characterizationof circulating EPCs. Isotype and fluorochrome-matched con-
trol antibodies (Abs) (Mouse IgG1-FITC and IgG1-PE) wereused for setting fluorescence markers around negative popula-tion and detecting non-antigen specific antibody binding.EDTA venous blood collected from patients and controls
and kept at room temperature was analyzed within 24 h ofvenipuncture. For red blood cell lysis, peripheral blood sam-ples were diluted in 15 ml bicarbonate-buffered ammonium
chloride solution for 15 min at room temperature. The cellswere centrifuged and re-suspended in 2 ml FC staining buffer(Cat. No. FC001; R&D/UK). The number of cells was
adjusted to 1 · 106 cells/ml. The cells were then prepared intothree test tubes, containing 100 ll of cell suspension each,
Left ventricular function in systemic lupus erythematosus patients S35
together with 10 ll FcR blocking reagent (to prevent non-specific binding) and 10 ll 7-AAD (to exclude dead cells fromFC analysis). The first tube contained as well VEGFR2-
Fluorescein and CD133/1-PE monoclonal Abs; the secondtube contained as well VEGFR2-Fluorescein and CD34-PEmonoclonal Abs while the third tube contained as well 10 llof the matched isotypic control. Positive staining was definedas being greater than non-specific background staining. Allsamples were measured in duplicate. The lymphocyte fraction
was identified on a forward/side scatter, and a minimum of1 · 105 lymphocytes were counted. Cells positive forVEGFR2/CD133 were characterized as early EPCs, whereascells positive for VEGFR2/CD34 within the lymphocyte frac-
tion were characterized as mature EPCs. Results wereexpressed as the number of EPCs per 1 · 106 lymphocytes.
3. Echocardiography
3.1. Transthoracic echocardiography (TTE) and tissue Dopplerimaging (TDI)
TTE and TDI were performed to all patients and controls
using a commercially available echocardiography machine(ESAOTE MY LAB 60) equipped with broadbandS1-5 MHz transducer in the Cardiology Department of Kasr
Al-Ainy Cairo University Hospitals. After a 10-min rest, sub-jects were examined in the left lateral decubitus position toobtain adequate images in different standard views. Left atrial,
aortic diastolic, LV end-diastolic dimensions (LVEDD), andLV end-systolic dimensions (LVESD) were measured usingM-mode echocardiography. Left ventricular ejection fraction(LVEF) was obtained by the biplane Simpson’s method.
Trans-mitral pulsed wave Doppler velocities were recordedfrom the apical four-chamber (4-CH) view.
Early (E) and late (A) wave peak velocities, E/A ratio, E
deceleration time (E-DT) were measured. By placing theDoppler sample volume midway between the mitral inflowand aortic outflow tract, trans-mitral and trans-aortic
Doppler flows were recorded simultaneously. The ejectiontime (ET), isovolumic contraction time (ICT) and isovolumicrelaxation time (IVRT) were measured and myocardialperformance index (MPI) was calculated as the ratio:
IVRT + IVCT/ET. The myocardial systolic (S), early diastolic(E0), and late diastolic (A0) peak velocities were obtained at thelateral and septal corners of the mitral annulus in the
4-chamber (4-CH) view by pulsed wave tissue Doppler keepingthe angle between the beam and the wall motion direction<15�. The E/lateral annulus E0 (E/E0) ratio was subsequently
calculated. All the above measures were recorded as the aver-age of three consecutive cycles.
3.2. Speckle tracking echocardiography (STE)
Myocardial deformation measurements were obtained usingSTE. The analysis was performed on grayscale images ofthe LV obtained in the apical 4-CH, 2-chamber (2-CH)
and short-axis mid-ventricular views. Three consecutiveend-expiratory cardiac cycles using high frame rate >80 s�1
harmonic imaging in each echocardiographic view were
acquired. Data were analyzed off-line using dedicated software(ESAOTE MY LAB 60) on one cardiac cycle. The analysis is
initiated by defining manually in the apical views three endo-cardial landmarks at the lateral and medial corners of themitral annulus and the LV cardiac apex and in the mid ventric-
ular short axis views two landmarks at the inferior septum andthe lateral wall. Manual adjustment of the segments of interestwas performed when necessary. Thereafter, the software auto-
matically analyzed different segments of interest. From theapical 4-CH view, longitudinal strain was assessed throughbasal, mid apical septal, basal, mid and apical lateral wall seg-
ments. From the apical 2-CH view, longitudinal strain wasassessed through basal, mid, apical inferior, basal, mid, andapical anterior wall segments. The global longitudinal strain(GLS) was calculated as the average of the LS of the 12
myocardial segments of the 4-CH and 2-CH views. From theshort axis view at the level of the papillary muscles, the circum-ferential strain was assessed through the mid-segments of the
anteroseptal, anterior, anterolateral, inferolateral, inferior,and inferoseptal walls. The global circumferential strain(GCS) was calculated as the average of the CS of the 6 mid
myocardial segments of the ventricular short axis view. Theglobal longitudinal systolic strain rate (GSSR), global diastolicstrain rate during the IVR period (GSRivr), early diastole
(GSRe) and late diastole (GSRa) were calculated as the averageof the SR of the 12 myocardial segments of the 4-CH and the2-CH views.
Statistical analysis: Normally distributed continuous
variables were expressed as mean ± SD while continuousvariables with non-normal distribution were presented as med-ian values and interquartile range (IQR). Categorical data
were expressed as percentages. Differences between groupswere assessed by unpaired 2-tailed t test and the Mann–Whitney U test for continuous variables, according to whether
they were normally distributed or not. Categorical data andproportions were analyzed by the use of chi-square orFisher’s exact test when required. Pearson and Spearman’s
correlation were used to assess the correlation between differ-ent variables. Univariate and multivariate linear regressionanalyses were used to investigate possible associations betweenSTE LV deformation abnormalities and other studied vari-
ables. A significance level of p < 0.05 was used in all tests.All statistical procedures were carried out using SPSS version15 for Windows (SPSS Inc., Chicago, IL, USA).
4. Results
A total of 50 SLE patients were included in the study; 47
females and 3 males. The median disease duration was4.5 years with an IQR of 2–7.25 years. The mean SLEDAIscore was 5.9 ± 5.75 (range: 0–20). All patients were receiving
prednisolone with a median duration of 54 months (IQR: 24–96 months). The median prednisolone dose was 7.5 mg (IQR:5–15 mg). Twenty-five subjects with comparable age and gen-der were included. Patients had a significantly higher ESR
(p< 0.001), HsCRP (p = 0.005), total serum cholesterol(p= 0.001), serum triglycerides (p = 0.001) and alaninetransaminase (p= 0.01) compared to the control. The com-
parison of the demographic and laboratory data between thepatients and controls is shown in Table 1.
The CD133+/VEGFR2+ and CD34+/VEGFR2+ EPC
counts were significantly lower in patients compared to controls(p= 0.009 and p = 0.0001, respectively). No significant
Table 1 Demographic and laboratory data of systemic lupus
erythematosus patients and controls.
Variable Patients
(n = 50)
Controls
(n = 25)
p value
Demographic
Age (years) 28.5 ± 8.5 30.2 ± 10.2 0.45
Female/male 47/3 23/2 1
BMI 26.5 ± 2.3 24.7 ± 1.9 0.001
Laboratory
ESR (mm/h) 72.5 (35–110) 16 (11–24) <0.001
Hs CRP (mg/dl) 0.7 (0.31–1.52) 0.35 (0.23–0.79) 0.005
Hb (gm/dl) 10.3 ± 1.3 13.2 ± 1.5 0.001
WBCs (·103/mm3) 7 ± 3.8 7 ± 2.4 0.9
Platelets (·103/mm3) 234.7 ± 118.3 244.5 ± 105.9 0.7
Creatinine (mg/dl) 1 ± 0.4 0.9 ± 0.3 0.1
Albumin (g/dl) 3.7 ± 0.5 3.9 ± 0.9 0.09
Cholesterol (mg/dl) 210.1 ± 74.5 169.6 ± 26.7 0.001
Triglycerides (mg/dl) 163.2 ± 67.6 93.2 ± 21.6 0.001
AST (IU/l) 21.5 ± 7 19.2 ± 5.8 0.1
ALT (IU/l) 20.3 ± 6.1 16.5 ± 5.4 0.01
EPC (cells/106Ly)
CD133+/
VEGFR2+5 (3–12) 109 (3–429) 0.009
CD34+/VEGFR2+ 3.5 (2–9) 63 (5–104) 0.0001
BMI: body mass index; ESR: erythrocyte sedimentation rate; Hs
CRP: high sensitivity C-reactive protein; Hb: hemoglobin; WBC:
white blood cells; AST: aspartate transaminase; ALT: alanine
transaminase; VEGFR: vascular endothelial growth factor recep-
tor; EPCs: endothelial progenitor cells. Ly: lymphocytes. Results
are presented as mean ± SD or as median (Interquartile range).
Bold figures mean significant p value.
Table 2 Transthoracic Echocardiography (TTE) and tissue
Doppler imaging (TDI) data for the systemic lupus erythe-
matosus patients and controls.
TTE
measurements
Patients
(n= 50)
Controls
(n= 25)
p
value
LVSWT (mm) 8.1 ± 1.8 7.9 ± 1.6 0.6
LVEDD (mm) 49.6 ± 6.4 47.3 ± 5.4 0.1
LVPWT (mm) 7.8 ± 1.5 7.7 ± 1.3 0.8
LVESD (mm) 33.0 ± 6.1 29.6 ± 5.6 0.02
EF (%) 64.0 ± 6.7 68.8 ± 7.7 0.007
Ao (mm) 25.2 ± 2.9 24.6 ± 2.9 0.4
LA (mm) 33.6 ± 5.5 31.3 ± 4.3 0.08
Transmitral velocity
E wave (cm/s) 90 ± 20 80 ± 20 0.1
A wave (cm/s) 80 ± 20 60 ± 10 0.002
E/A ratio 1.3 ± 0.4 1.4 ± 0.4 0.2
E-DT (ms) 179.3 ± 37.8 170.4 ± 41.3 0.4
IVRT (ms) 75.7 ± 13.4 58.6 ± 6.1 0.01
MPI 0.62 ± 0.12 0.49 ± 0.05 0.0001
Tissue Doppler imaging
Med E0 (cm/s) 8.7 ± 2.9 11.4 ± 4 0.002
Med A0 (cm/s) 6.2 ± 2.5 5.3 ± 1.7 0.07
Med S0 (cm/s) 7.5 ± 1.6 7.5 ± 2.1 0.9
Lat E0 (cm/s) 9.0 ± 4.0 11.7 ± 3.4 0.01
Lat A0 (cm/s) 7.0 ± 3.8 6.4 ± 1.8 0.3
Lat S0 (cm/s) 8.3 ± 1.6 8.8 ± 2.2 0.4
Lat E/E0 11.1 ± 5 7.6 ± 2.2 0.002
TEE: Transthoracic Echocardiography; LVSWT: left ventricular
septal wall thickness; LVEDD: left ventricular end diastolic
dimension; LV PWT: left ventricular posterior wall thickness;
LVESD: left ventricular end systolic dimension; EF: ejection frac-
tion; Ao: aorta; LA: left atrium; MPI: myocardial performance
index; E-DT: E wave deceleration time; Lat: lateral; Med: medial;
IVRT: isovolumic relaxation time. Bold values mean significant p
value.
S36 S.W.G. Bakhoum et al.
correlation was detected between CD133+/VEGFR2+ or
CD34+/VEGFR2+ EPC count and age of patients (r = 0.21,p= 0.2 and r = 0.13; p= 0.4 respectively), disease duration(r = �0.08, p= 0.6 and r= �0.01; p = 1 respectively), pred-
nisolone dose (r= 0.02, p= 0.9 and r = 0.04; p = 0.8 respec-tively), prednisolone duration (r = �0.05, p = 0.7 andr= �0.03; p= 0.9 respectively), SLEDAI score (r = �0.19,p= 0.2 and r= �0.23; p = 0.1 respectively), BMI (r = 0.03,
p= 0.8 and r= 0.001; p = 1 respectively), Hs CRP(r = 0.26, p= 0.06 and r= 0.27; p = 0.06 respectively) orESR (r= 0.17, p = 0.3 and r= 0.26; p = 0.07 respectively).
4.1. Echocardiographic data
4.1.1. M-mode, two-dimensional Doppler measurements
The LVESD was significantly greater (p= 0.02) while theLVEF was significantly lower in patients (p= 0.007) com-
pared to controls. Trans-mitral flow A wave velocity was sig-nificantly higher (p = 0.002) and the IVRT significantlyprolonged (p= 0.01) in patients compared to controls. TheMPI was also significantly higher in patients (p = 0.0001).
4.1.2. Tissue Doppler imaging (TDI) measurements
The medial and lateral mitral annulus E0 wave velocities were
significantly lower in patients compared to controls (p = 0.002and p = 0.01, respectively). The lateral E/lateral E0 ratio wassignificantly higher in patients compared to controls
(p = 0.002). The detailed TTE and TDI measurements of thepatients and controls are shown in Table 2.
4.1.3. Speckle tracking echocardiography (STE) measurements
The GLS and GCS were significantly lower in patients com-pared to controls (p < 0.001 in both) (Fig. 1). The GSRivrwas significantly lower in patients compared to controls
(p = 0.01). The detailed STE measurements of patients andcontrols are listed in Table 3. Univariate logistic regressionwas used to investigate possible associations between the
GLS, GCS, GSRivr and the following variables: age ofpatients, duration of disease, prednisolone dose, prednisoloneintake duration, use of azathioprine vs. cyclophosphamide,
SLEDAI score, MPI, LVEF, CD133+/VEGFR2+ EPC countand CD34+/VEGFR2+ EPC count. There was no significantcorrelation between any of the studied variables and GLS
either by univariate or multivariate analysis. Using univariateanalysis, there was no significant correlation between studiedvariables and GCS except for prednisolone dose. After adjust-ment for all variables using multiple logistic regression model,
prednisolone dose remained the only independent variableaffecting GCS (adjusted regression coefficient = �0.24, 95%CI = �0.46 to �0.03; p = 0.03). As regards GSRivr, LVEF
was the only variable affecting it by both univariate andmultivariate logistic regression analyses (adjusted regression
Figure 1 Automatically generated left ventricular (LV) deformation curves by the software (my lab60). (A) LV circumferential strain in
the short axis view at the level of papillary muscles. (B) LV longitudinal strain in the four–chamber view. (C) LV longitudinal strain in the
two–chamber view. (D) LV strain rate in the two–chamber view. The curves in white represent the average (global) strain or strain rates of
different studied LV segments.
Left ventricular function in systemic lupus erythematosus patients S37
coefficient = 2.4, 95% CI = 0.001–0.01; p= 0.021). Thedetailed multivariate linear regression analysis of the different
factors affecting GLS, GCS and GSRivr is shown in Table 4.
5. Discussion
The current study demonstrated significantly reducedCD133+/VEGFR2+and CD34+/VEGFR2+ EPC count inSLE patients compared to controls. Experimental and clinical
studies have demonstrated the important role of EPCs in tissueregeneration including neoangiogenesis, reendothelialization,repair of injured arteries and improvement of LV function fol-lowing myocardial infarction [6,17–21]. The current study find-
ing of low EPCs in SLE patients is in agreement with theresults of several other studies. Denny et al. [22] reported a sig-nificant decrease of CD34+/CD133+ EPCs and myelomono-
cytic circulating angiogenic cells (CACs) and a significantcorrelation of EPC count with SLEDAI score but not withthe use of specific medications or daily corticosteroid doses.
However, even those individuals with no clinical or serologicdisease activity (SLEDAI = 0) had pronounced EPC decreasecompared with controls. Lee et al. [23] demonstrated a mark-
edly reduced level of EPC colony-forming units and the deple-tion of EPCs was more dramatic in SLE patients with elevatedlevels of IFN-I. The reduced EPC levels were not explained byuse of common medications including steroids, anti-malarials,
cytotoxic agents, or statins.In our study, we could not find any significant correlation
between EPC count and disease duration, SLEDAI score, pred-
nisolone dose or duration of intake, HsCRP or ESR. Thereduction of EPCs was even reported in SLE patients in an
inactive stage of disease, or in prolonged clinical remission[24,25]. Ebner et al. [8] reported an enhanced
VEGFR2+/CD133+ EPC number whereas the number ofVEGFR2+/CD34+ cells and the proliferation rate were signif-icantly decreased. In the current study, the levels of immature
VEGFR2+/CD133+ and mature VEGFR2+/CD34+ cellswere reduced. The decrease in the number of circulatingEPCs was also described in other diseases with vascular inflam-
matory components, for example, rheumatoid arthritis andchronic renal failure [26,27]. The low levels of circulatingEPCs in our study could be attributed to increased oxidativestress related to the inflammatory process associated with
SLE and which was shown to inhibit EPC differentiation,survival, and function [28]. An alternative explanation is thatcontinuous endothelial damage or dysfunction leads to an even-
tual depletion or exhaustion of a presumed finite supply of EPCsinvolved in vascular homeostasis and endothelial repair. SLEhas been shown to be an independent risk factor for endothelial
dysfunction [3]. In a recent study of 38 lupus women withoutdetectable myocardial ischemia on myocardial perfusion imag-ing, brachial artery flow mediated vasodilatation as a markerof endothelial function correlated strongly with E/E0 as a marker
of LV diastolic function independent of systolic blood pressure,age, or lupus clinical damage index [29].
The second important finding of the current study is the
echocardiographic abnormalities of both systolic and diastolicfunction in SLE patients with no clinically apparent CV dis-ease. Echocardiographic cardiac abnormalities were described
more than 3 decades ago in SLE [30–32]. To the best of ourknowledge, this the first study to investigate the correlationbetween LV deformation abnormalities as detected by STE
Table 3 Speckle tracking echocardiography (STE) data for the systemic lupus erythematosus patients and controls.
STE data Patients (n= 50) Control (n= 25) p value
4-Chamber view longitudinal strain (%)
Basal septal 14.3 ± 5.5 16.6 ± 2.6 0.01
Mid septal 16.2 ± 4.3 18.7 ± 2.3 0.002
Apical septal 18.3 ± 6.3 20.3 ± 3.7 0.2
Basal lateral 14.9 ± 3.7 19.8 ± 4.8 <0.001
Mid lateral 14.8 ± 3.8 19.1 ± 3.8 <0.001
Apical lateral 19.9 ± 26.7 18.2 ± 2.8 0.8
2-Chamber view longitudinal strain (%)
Basal inferior 11.1 ± 5.8 19.6 ± 4.3 <0.001
Mid inferior 13.5 ± 4.2 18.6 ± 2.9 <0.001
Apical inferior 14.9 ± 5.4 19.7 ± 4.1 <0.001
Basal anterior 13.2 ± 5.9 21.0 ± 5.2 <0.001
Mid anterior 13.1 ± 4.9 19.2 ± 5.0 <0.001
Apical anterior 12.7 ± 5.2 17.1 ± 4.1 <0.001
GLS (%) 14.5 ± 2.8 19.0 ± 1.3 <0.001
SAX view circumferential strain (%)
Mid anteroseptal 23.6 ± 11.0 30.3 ± 11.7 0.02
Mid anterior 20.5 ± 11.5 29.6 ± 11.5 0.002
Mid anterolateral 16.5 ± 7.4 24.6 ± 9.2 <0.001
Mid inferolateral 16.2 ± 6.0 22.7 ± 6.9 <0.001
Mid inferior 17.8 ± 6.5 24.3 ± 8.1 <0.001
Mid inferoseptal 21.0 ± 7.7 25.6 ± 9.1 0.04
GCS (%) 19.3 ± 6.8 26.2 ± 6.9 <0.001
GSR longitudinal systolic (1/s) 1.0 ± 0.2 1.1 ± 0.2 0.2
GSR longitudinal diastolic (1/s)
GSRivr 0.14 ± 0.09 0.2 ± 0.1 0.01
GSRe 1.2 ± 0.3 1.3 ± 0.2 0.1
GSRa 0.8 ± 0.3 0.7 ± 0.2 0.2
STE: speckle tracking echocardiography; SAX: GLS: global longitudinal strain; GCS: global circumferential strain; GSR: global strain rate; ivr:
isovolumic relaxation period; GSRe: global strain rate during early diastole; GSRa: global strain rate during atrial contraction; SAX: short axis.
Bold values mean significant p value.
Table 4 Factors affecting global longitudinal strain (GLS), global circumferential strain (GCS) and global strain rate (GSR) during
isovolumic relaxation period.
Variables GLS GCS GSRivr
ARC (95% CI) p ARC (95% CI) p ARC (95% CI) p
Age 0.07 (�0.06 to �0.19) 0.3 0.09 (�0.2 to �0.4) 0.5 1.1 (�0.002 to �0.01) 0.3
Disease duration 0.3 (�1.18 to �0.19) 0.7 0.68 (�2.6 to �4) 0.7 �0.1 (�0.05 to �0.05) 0.9
Steroid dose �0.007 (�0.10 to �0.09) 0.9 �0.24 (�0.5 to �0.03) 0.03 0.1 (�0.003 to �0.003) 0.9
Steroid duration �0.09 (�1.52 to �1.34) 0.9 �1.01 (�4.4 to �2.2) 0.5 0.5 (�0.04 to �0.06) 0.6
AZA/CYC 2.5 (�0.49 to �5.48) 0.1 1.63 (�5.2 to �8.4) 0.6 1.7 (�0.02 to �0.19) 0.09
SLEDAI score �0.04 (�0.2 to �0.12) 0.7 0.03 (�0.3 to �0.4) 0.9 �0.6 (�0.01 to �0.004) 0.6
MPI 1.4 (�5.64 to �7.51) 0.7 13.6 (�2.5 to �29.7) 0.1 1.3 (0.001 to 0.01) 0.2
LVEF �0.08 (�0.22 to �0.05) 0.2 0.08 (�0.2 to �0.4) 0.6 2.4 (0.001 to 0.01) 0.02
EPCs
VEGFR2+/CD133+ 0.002 (�0.01 to �0.02) 0.8 �0.01 (�0.04 to �0.02) 0.5 0.7 (0.00001 to 0.001) 0.5
VEGFR2+/CD34+ �0.006 (�0.06 to �0.05) 0.82 0.01 (�0.12 to �0.14) 0.9 �1.01 (�0.003 to �0.001) 0.3
GLS: global longitudinal strain; GCS: global circumferential strain; GSRivr: global strain rate during isovolumic relaxation period; ARC:
adjusted regression coefficient; CI: confidence interval; AZA/CYC: azathioprine/cyclophosphamide; SLEDAI: systemic lupus erythematosus
disease activity index; MPI: myocardial performance index; LVEF: left ventricular ejection fraction; EPCs: endothelial progenitor cells. Bold
values mean significant p value.
S38 S.W.G. Bakhoum et al.
and EPC count in the peripheral circulation of SLE patients.As regards conventional TTE and TDI findings, SLE patients
in the present study had a significantly higher LVESD com-pared to controls (p = 0.02). Although the LVEF of the
patients was in the normal range, it was significantly lowercompared to controls (p = 0.007) suggesting subclinical sys-
tolic dysfunction. The IVRT was significantly prolonged andthe MPI was significantly higher in patients compared to
Left ventricular function in systemic lupus erythematosus patients S39
controls denoting diastolic dysfunction as well. In agreementwith our results, a significantly lower LVEF was reported inSLE patients compared to controls (p< 0.001) in a study of
50 SLE patients. A significantly higher interventricular septum(IVS) and posterior wall (PW) dimensions, and Doppler mitralA/E ratio in patients compared to controls have been demon-
strated [33]. In our study, there was no statistically significantdifference in IVS, PW dimensions or trans-mitral flow DopplerE/A ratio between the patients and controls. A study compar-
ing patients with SLE to those with antiphospholipidsyndrome (APS), lupus patients had higher LVEDD andLVESD (p= 0.022 and 0.022, respectively), with a trendtoward a lower fractional shortening (p = 0.07) compared to
primary APS [10]. Cacciapuoti et al. [34] used TDI to calculateIVRT and MPI in 44 SLE patients without clinical signs ofheart disease, and found as well significantly higher IVRT
and MPI in patients compared to controls. The current studyalso demonstrated a significantly higher E/lateral E0 ratio inpatients compared to controls (p = 0.002) pointing again to
diastolic dysfunction. Similarly, Lee et al. [35] reported ahigher E/E0 in SLE patients compared to controls despite anormal Doppler flow E/A ratio (p < 0.01) This study also
described a lower E/E0 ratio and higher LVEF in SLE patientsreceiving angiotensin converting enzyme inhibitors (ACE-Is)or angiotensin receptor blockers (ARBs) compared to thosenot receiving these medications indicating their role in preserv-
ing LV diastolic and systolic functions. None of our patientswere receiving ACE-Is or ARBs because we excluded SLEhypertensive patients and the patients included were free of
clinically manifest CV disease.As regards STE findings, the current study revealed a signif-
icantly lower LV GLS (p< 0.001), LV GCS (p< 0.001) and
GSRivr (p= 0.01) in patients compared to controls. Therewas no significant correlation between any of the studied vari-ables and GLS. By multiple logistic regression analysis, the
independent variables affecting GCS and GSRivr were theprednisolone dose and the LVEF respectively. (p = 0.028and p = 0.021; respectively). These findings were in agreementwith some aspects of the study by Buss et al. [36] who used
TDI to calculate LV strain and strain rates in 67 young SLEpatients. This study not only demonstrated significantlyreduced GLS; a finding similar to our study but also detected
significantly reduced GSSR, GSRe, GSRa in patients com-pared to controls. Further, elevated SLEDAI score, resultedin significantly lower values for LV longitudinal function strain
and strain rate. In the current study, we could not find any sta-tistically significant difference in GSSR, GSRe, GSRa betweenpatients and controls. In a recent study using three-dimensional (3D) STE, although no difference in LV global
systolic function was noted by standard echocardiographybetween patients and controls, 3D LVEF, LV GLS, LVGCS,LV global area stain (GAS) and global radial strain (GRS)
were largely impaired in patients [37]. This study demonstratedalso that GLS, GAS, GRS but not GCS were significantlydecreased in those with severe disease activity than among
those with no or mild activity (all p< 0.05). GLS was alsoindependently correlated with SLEDAI score (p= 0.001).Yip et al. [12] showed that SLEDAI P1 was an independent
predictor of LV longitudinal systolic dysfunction in SLEpatients using TDI. In the present study, no correlation wasdetected between SLEDAI score and the different myocardialdeformation parameters. The lack of a significant correlation
between SLEDAI score and evident LV diastolic dysfunctionin SLE patients has been described before in previous studies[38,39]. In the present study, these LV subclinical abnormali-
ties cannot be explained by increased prevalence of traditionalCV risk factors such as smoking, HTN or DM becausepatients having them were excluded. The patients had however
significantly higher cholesterol and triglyceride levels com-pared to controls. This may be the result of prednisolonewhich was prescribed to all patients. It is generally perceived
that glucocorticoids have adverse effect on the lipid profilecausing increase in both total cholesterol and triglycerides[40,41]. This high level of cholesterol and triglycerides mayhave induced subclinical coronary atherosclerosis in our
patients. A high prevalence of myocardial perfusion abnormal-ities were detected in asymptomatic SLE patients without overtCV disease using single photon emission computed tomogra-
phy [42,43]. In a study by Doria et al. [44], subclinicalatherosclerosis has been shown to be more prevalent in SLEpatients. Patients with carotid abnormalities were significantly
older, had higher blood pressure and total serum cholesterollevels, and had taken a higher prednisone cumulative dosagethan those without any lesions. By multivariate analysis, the
cumulative prednisone dose remained associated with plaqueformation after adjusting it for the classical Framinghamatherosclerosis risk predictors. A significant associationbetween carotid plaque formation in SLE patients and cumu-
lative corticosteroid dosage as well as duration of treatmenthas been also reported by Manzi et al. [45]. In another studyon Egyptian SLE patients, an increased prevalence of subclin-
ical LV dysfunction was reported. SLE patients with positivetissue Doppler findings were of old age, had long disease dura-tion, high disease activity and nephritis [46]. In the current
study, the prednisolone dose was the only independent variableadversely affecting LV GCS (p= 0.028). In a study of diabeticpatients, those with coronary atherosclerosis as evidenced by
increased calcium score in multi-slice computerized tomogra-phy scanner showed an impaired LV GLS, even though theLVEF was still preserved compared to those with no evidenceof coronary atherosclerosis [47]. Hence, premature subclinical
atherosclerosis may be the underlying cause of these subtlechanges in LV function.
When we designed the current study, we hypothesized that
EPCs might have a relation to any possible detected systolic ordiastolic LV function abnormalities in SLE patients. Thesespeculations were based on the findings of previous studies
correlating EPC count to LV remodeling and function[9,21,48,49]. Peripheral blood CD34+ cells and EPC mobiliza-tion occurs in heart failure (HF) and shows a biphasicresponse, with elevation and depression in the early and
advanced phases, respectively [48]. In a study by Kissel et al.[9], the number of EPCs was found to be reduced, irrespectiveof the etiology of HF, whether ischemic or dilated cardiomy-
opathy. On the other hand, in a study by Leone et al. [49],the concentration of CD34+ bone marrow derived stem cellswas not only higher in acute myocardial infarction (AMI)
patients compared to patients with stable CAD but was alsoan independent predictor of global and regional improvementof LV function at the end of 1 year follow-up. In the
TOPCARE-AMI trial, intracoronary infusion of circulatingEPCs in patients with AMI resulted in an increased EF,reduced infarct size, and absence of reactive hypertrophy, sug-gesting functional regeneration of the infarcted ventricles at
S40 S.W.G. Bakhoum et al.
the end of 1 year follow-up. In the current study, the inabilityto detect a statistically significant correlation between the EPCcount and LV deformation abnormalities could be attributed
to their detection in a quite early stage using STE or becauseof the small number of patients studied.
The first limitation is the cross sectional design of the study.
The patients were not followed up to be able to examine theprogression of LV systolic and diastolic abnormalities detectedby STE or the effect of the low circulating EPCs on these
abnormalities over time. The second limitation is the relativelysmall number of patients. This can be explained by the rigor-ous exclusion criteria. We actually excluded patients with clas-sical risk factors such as smoking, HTN or DM which were
quite prevalent in lupus patients to avoid the impact of thesefactors on LV function.
In conclusion the relatively new STE can be used to diag-
nose subtle abnormalities in LV function in SLE patientswhich could not be detected by conventional TTE or TDI.The low count of circulating EPCs detected in these patients
was probably the result of the inflammatory process associatedwith SLE rather than early LV dysfunction which could onlybe detected by STE.
Conflict of interest
None.
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